dDepartment of Mechanical Engineering, University of Washington, Seattle, WA 98195;eCenter for Cardiovascular Biology, University of Washington, Seattle, WA 98195;fInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195;

dDepartment of Mechanical Engineering, University of Washington, Seattle, WA 98195;eCenter for Cardiovascular Biology, University of Washington, Seattle, WA 98195;fInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195;

gAab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624;hDepartment of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624;

gAab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624;hDepartment of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624;iDepartment of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624;

dDepartment of Mechanical Engineering, University of Washington, Seattle, WA 98195;eCenter for Cardiovascular Biology, University of Washington, Seattle, WA 98195;fInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195;kDepartment of Bioengineering, University of Washington, Seattle, WA 98195

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Significance

Mutations in the LAMP-2 gene are associated with Danon disease. Although dysregulation of autophagy has been described in Danon disease, the mechanisms by which LAMP-2 deficiency leads to autophagy dysregulation remain elusive. Autophagy ends with fusion between autophagosomes and late endosomes/lysosomes for degradation. It has been shown that STX17 is essential for autophagic fusion in noncardiomyocytes. Here, we demonstrate that LAMP-2B promotes autophagosome–lysosome fusion in cardiomyocytes (CMs), independently of STX17. LAMP-2B deficiency in CMs causes defects in autophagic fusion and functional abnormalities, recapitulating the phenotype of Danon CMs. Gene correction of the LAMP-2 mutation restores CM function. Our results thus reveal a significant autophagosome–lysosome fusion mechanism in CMs and provide a foundation for gene correction therapy in patients with Danon disease.

Bacteria could help tackle the growing mountains of e-waste that plague the planet. Although researchers are a long way from optimizing the approach, some are already confident enough to pursue commercial ventures.

Holographic acoustic tweezers, in which ultrasonic waves produced by arrays of sound emitters are used to individually manipulate up to 25 millimeter-sized particles in three dimensions, could be used to create 3D displays consisting of levitating physical voxels.